Normal human somatic cells have finite replicative life-spans when cultured in vitro. This phenomenon of "clonal senescence" may be regarded as a useful model for the study of certain aspects of cell aging. The proposed experiments attempt to elucidate the mechanism(s) of such clonal senescence by a variety of somatic cell genetic experiments involving heterokaryons, synkaryons and hybrids between post-replicative "old" cells and both normal diploid and heteroploid actively replicating cells. In one line of experiments, temperature sensitive cell cycle mutants will be employed in attempts to identify a specific protein which can re-initiate DNA synthesis in "senescent" post-replicative cells. The general hypothesis being tested is that clonal senescence is initiated by a process analogous to cell differentiation.